Abdominal aortic aneurysms (AAA) occur in approximately 3% of humans > 65 years of age and are characterized by localized structural deterioration of the aortic wall, leading to progressive aortic dilation, The morbidity and mortality associated with AAA are considerable. Surprisingly, however, little is known about the mechanisms responsible for aneurysm formation and progression. Recent histological studies in humans indicate that AAA are highly inflammatory in nature. The inflammatory response is associated with death of smooth muscle cells (SMC) and degradation of matrix proteins by matrix metalloproteinases (MMP) that causes weakening of the aortic wall, and, consequently, dilation. Given that reactive oxygen species (ROS) are produced during inflammation and can induce SMC death and MMP activation, we hypothesize that ROS play a pivotal role in AAA formation. As an initial step to investigate this hypothesis, we examined human aneurysm tissue removed at the time of elective AAA repair. Our studies indicate that levels of superoxide and lipid peroxidation products, an index of tissue injury caused by oxidative stress, are markedly increased in AAA as compared with adjacent, non-aneurysmal aortic tissue obtained from the same patients. We also detected increased expression and activity of NAD(P)H oxidase, a superoxide-generating enzyme, in AAA. Whether or not ROS contribute to the pathogenesis of AAA, however, remains to be determined. An experimental model of aneurysm formation has recently been developed in which angiotensin II is infused into hyperlipidemic male mice. After 28 days, the mice develop AAA with histologic and pathological features that resemble AAA in humans. Angiotensin II is known to induce aortic inflammation and production of superoxide through activation of NAD(P)H oxidase, which is thought to play a role in vascular disease in humans. Preliminary data using this model indicate that levels of superoxide in the aorta of these mice are markedly increased in response to infusion of angiotensin II, preceding the formation of AAA. Here, we propose to employ a combination of pharmacological and genetic approaches to modulate ROS and NAD(P)H oxidase, and to modulate the Rho/ROCK signaling pathway, in order to investigate the role of oxidative stress in AAA formation. Our findings could have important implications with regard to the treatment of AAA in humans. [unreadable] [unreadable]